Tolerance to effects of cannabinoids is a phenomenon that warrants more research. Cannabinoids are currently being used to treat symptoms associated with HIV/AIDS and cancer chemotherapy. Tolerance has numerous health related implications; not only in those with HIV/AIDS or cancer, but in its role in drug abuse as well. Delta-9-THC (THC) has been isolated from the Cannabis sativa plant (marijuana) and is psychotropic and immunosuppressive. Repeated administration leads to the development of tolerance to many of THC's pharmacological effects, a phenomenon we have observed in the immune system. The long- term objective of this project is to test the hypothesis that tolerance develops to THC-induced immunomosuppression. To test the hypothesis three aims will be pursued: 1) Determine if the development of tolerance to THC-induced immunosuppression observed in the In Vivo IgM Antibody Forming Cell (AFC) assay is dose-responsive in nature, and if the immune system responds similarly to the cannabinoid receptor agonist CP-55,940 (CP). We will also determine if T helper 1 (Th1) and T helper 2 (Th2) cytokine levels differ in tolerant and non-tolerant animals. 2) Demonstrate in vivo treatment with THC/CP-55,940 results in modulation of the In Vitro IgM Antibody Forming Cell assay in a manner similar to that observed in the In Vivo AFC assay used in pursuit of Specific Aim 1. Allowing then, for immune cell separation/reconstitution studies to be conducted; to determine the immune cell type(s), and respective cannabinoid receptor(s), involved in or responsible for the development of tolerance to cannabinoid-induced suppression of T-cell dependent humoral immunity. 3) Test the hypotheses that the development of tolerance to the immunosuppressive effects of cannabinoids is associated with down regulation of immune cell cannabinoid receptors and/or desensitization of immune cell cannabinoid receptor-mediated G-protein activation .The goal of this research is to determine the mechanisms by which tolerance occurs to cannabinoid-induced suppression of T-cell dependent humoral immunity. This is important because individuals with compromised immune systems, such as those living with cancer and/or HIV/AIDS, find cannabinoids particularly useful as anti-emetics, appetite stimulants, in alleviating neuropathic pain, and increasing their likelihood of taking more aversive drugs. However, immunosuppression can contraindicate cannabinoid use in these patients. This work will significantly contribute to an understanding which will help physicians who treat cancer and HIV/AIDS patients utilize cannabinoids safely and effectively. [unreadable] [unreadable] [unreadable]